Clinical Trial Update

Three-Year Data From BIOFLOW V: The Orsiro vs the Xience Drug-Eluting Stents

CLD talks with David E. Kandzari, MD, Director of Interventional, Piedmont Heart Institute and Chief Scientific Officer, Piedmont Healthcare, Atlanta, Georgia.

CLD talks with David E. Kandzari, MD, Director of Interventional, Piedmont Heart Institute and Chief Scientific Officer, Piedmont Healthcare, Atlanta, Georgia.

Dr. Kandzari, you presented BIOFLOW V results at the CRT meeting in late February of this year. We last spoke about the Orsiro stent (Biotronik) in 2019, when the 2-year results were available.1 How do the 3-year results now compare?

As part of the trial, we have planned dedicated follow-up through a minimum of 5 years in this study to determine whether differences that were identified, for example at 1 year, might further progress or instead converge over time. We will also be evaluating whether differences in other endpoints might be identified over longer term follow-up. The recently presented 3-year results have also now been published.2 Recall that at 1 year we observed a significant difference in target vessel myocardial infarction, which is one of the components of the composite primary endpoint of target lesion failure. Target lesion failure is defined as cardiovascular-related death, target vessel-related myocardial infarction, and clinically driven repeat revascularization.  

At 1 year, we identified the significant difference in target lesion failure favoring the Orsiro drug-eluting stent (Biotronik) compared with the Xience stent (Abbott Vascular). We also observed a significant difference in the component endpoint of target vessel myocardial infarction. At 2 years, we observed the same differences, but if anything, those differences continued to diverge or widen over a longer term follow-up. Moreover, we also identified significant differences in late target lesion revascularization and stent thrombosis, including late and very late stent thrombosis. At the 3-year follow-up, again, we sought to observe whether those differences persisted, whether those differences were even further widened over long-term follow-up or perhaps instead were mitigated, or whether other differences might emerge. And the 3-year data have shown us a continued, highly significant statistically but also very clinically meaningful difference in the outcomes of target vessel-related myocardial infarction, target lesion revascularization, and the composite of target lesion failure. We have also identified persistent differences in late and very late stent thrombosis. In fact, we now have observed a significant difference in the endpoint term of very late stent thrombosis, which relates to events that occur after 1 year of the index procedure. Specifically, we observe an extremely low event rate after the first 30 days, and in particular, no further events of stent thrombosis with the Orsiro stent after 1 year of index revascularization, now through 3 years of follow-up. Altogether, the 3-year findings reaffirm the observations noted at 1 and 2 years of follow-up. If anything, the differences in these endpoints of repeat revascularization, which is an efficacy endpoint, and the safety endpoints of stent thrombosis and myocardial infarction, continue to diverge further, favoring the Orsiro drug-eluting stent. Recall that the Orsiro stent is distinguished by not only having a bioresorbable polymer but also an ultra thin-strut design of only 60 microns thickness for stent diameters 3.0 mm or less. In comparison, the Xience stent has a strut thickness of 81 microns.

Can we say anything more definitive about the Orsiro stent’s bioresorbable polymer at 3 years having compared the Orsiro stent to the Xience stent, which has a durable polymer? 

One of the common questions from the findings of BIOFLOW V is whether the benefits observed with the Orsiro stents are a result of the bioresorbable polymer disappearing over time and in theory, restoring the stent type to that of a bare-metal stent that has been associated with long-term stability and possibly a safety advantage. Alternatively, is it the ultra thin-strut stent design that confers the largest advantage, because ultra thin-struts stents have been well demonstrated to accelerate healing, perhaps may reduce injury to the vessel wall, and promote endothelialization and healing? Ultra-thin struts may even potentially reduce sheer stresses across the stented segment that could result in fewer thrombotic events. Essentially, is it a benefit of the bioresorbable polymer that translates to this difference in outcomes or is it instead the ultra thin-strut stent? The short answer is that we don’t know. BIOFLOW V certainly wasn’t designed to address that question. We know that the polymer does not completely resorb until about 2-year period after stent implantation. Yet in this trial, we have observed significant differences in myocardial infarction occurring very early, from as early as the time of the procedure to the first year, then continuing to expand over the next years of follow-up, in a time period where the polymer is still existent. These benefits likely can’t be attributed to the bioresorbable polymer compared with a more durable polymer.

On the other hand, after 1 year, we see an emergence of differences in repeat revascularization and stent thrombosis rates that favors the Orsiro stent. Whether that’s related to the ultra thin-strut stent or to the beginning of disappearance of the polymer remains hypothetical. 

These findings add to a larger body of evidence supporting more favorable outcomes with an ultra thin-strut, bioresorbable polymer stent such as the Orsiro stent. We are increasingly developing an evidence base showing differences in outcome with this stent type compared with other stents.

For example, the randomized SORT OUT IX showed that the Orsiro stent was superior to another competitor stent for repeat revascularization. There is also the BIOSTEMI trial, which was published in the Lancet and was presented as a late-breaking trial at the European Society of Cardiology meeting in August 2019. BIOSTEMI showed the superiority of the Orsiro stent compared with the Xience stent, the same competitor as in BIOFLOW V, but in patients with ST-elevation myocardial infarction. And yet another trial called BIO-RESORT showed that overall, the Orsiro stent compared with other contemporary generation drug-eluting stents has the lowest rate of repeat revascularization and may in fact be superior to other drug-eluting stents in small-caliber vessels.

An emerging body of evidence seems to demonstrate a consistent theme with this particular ultra thin-strut stent, showing its clinical advantage compared with other stents. That’s quite meaningful when we once believed that we have reached a plateau with drug-eluting stents, meaning that the outcomes with stents are so good today with regard to both safety and efficacy that they all seem to exhibit a class effect and fare similarly. The thinking was that maybe we couldn’t get any better than what we currently have. The experience with Orsiro tells us that there is an opportunity for incremental, iterative improvement, and we can actually demonstrate superiority with yet a newer stent design compared with what we have today in clinical practice.

Has there been a shift in awareness as the data has come out?

I certainly couldn’t speak to a shift in terms of market share or adoption by clinicians. In general, though, within the interventional community, and even within the broader medical device community, there is an increasing focus on highlighting an ultra thin-strut stent design in discussions regarding drug-eluting stents. We see this topic of ultra-thin struts in stent design being incorporated more and more into programs and sessions at various scientific sessions. Just the increasing discussion about ultra thin-strut stent designs tells me that it is coming more to the forefront for both stent manufacturers and clinicians.

Can you describe the lesions included in BIOFLOW V and more about the patient population?

BIOFLOW V wasn’t an unrestricted or what is often termed an “all-comers” clinical trial. There were selected exclusion criteria. It is a study population that involved patients with some selected anatomic complexities and complex clinical indications. Nevertheless, many patients included in the trial are very much representative of those patients routinely encountered in daily clinical practice. The trial included patients who could be treated for multi-vessel disease for up to 3 lesions in 2 target vessels. Patients with acute coronary syndromes and non-ST-elevation myocardial infarction could be included. Patients with calcified lesions or lesions that even required atherectomy in selected instances could also be included in the trial. Those excluded from the trial were patients with acute ST-elevation myocardial infarction, patients with very advanced chronic kidney disease requiring hemodialysis, and patients with some selected anatomic complexities, such as chronic total occlusions and those with disease in bypass grafts.

Is there any potential economic data regarding use of the Orsiro stent that has been released?  

Yes, to a modest extent. We recently published some data showing the economic impact of reducing myocardial infarction with any effective therapy and in this case, with the Orsiro drug-eluting stent.3 The thought was that if we can reduce not only peri-procedural myocardial infarction, but also spontaneous myocardial infarction events, that it may translate to an economic benefit as well. It seems relatively intuitive, because peri-procedural myocardial infarction, for example, might translate into greater resource utilization or longer hospital stay duration. Certainly, for non-procedural related events such as spontaneous myocardial infarction that may have even greater clinical impact, any intervention that could reduce those events would avoid not only long-term comorbidities, but may also translate to reduced direct hospital costs if not avoiding hospital admission altogether. Similarly, cost effectiveness could be demonstrated with significantly lower restenosis and repeat revascularization.

BIOFLOW V follow-up goes out to 5 years, so we will await those ongoing data. Are there any other future plans for study of the Orsiro stent? 

There are a couple of next areas of interest. Certainly one, as you note, is the dedicated, longer term follow-up. We plan to follow BIOFLOW V patients, at a minimum, through 5 years to continue to examine this very interesting trajectory of events that differentiate this stent type from others. For example, after one year, the rate of repeat revascularization or clinical restenosis begins to level off with Orsiro. Meanwhile, whether it is with Xience or other contemporary generation drug-eluting stents in clinical trials, we have observed an annualized, roughly 1.5% to 2% year-after-year increased risk of repeat revascularization. We don’t see that with Orsiro; it is quite distinctive compared with what we are seeing with other drug-eluting stents and is even more reason to follow these patients over a long term to better understand that benefit. Another real opportunity for Orsiro would be to move forward with a shortened dual antiplatelet therapy clinical trial. Certainly there is a great deal of attention to high bleeding-risk patients and abbreviating their dual antiplatelet therapy. Such a trial will also increase our understanding of the safety with this particular drug-eluting stent, similar to what has been demonstrated recently with some alternative drug-eluting stents. I believe that the safety of short-term dual antiplatelet therapy is not a ‘class effect’ and instead must be studied with each specific stent type. For this reason, it may be a large opportunity for the Orsiro stent, and my understanding is that Biotronik is planning to move forward with a trial. 

Disclosure: Dr. Kandzari reports institutional research/grant support from Biotronik, Boston Scientific, Medinol, Medtronic, Orbus Neich and Teleflex; and personal consulting honoraria from Cardiovascular Systems, Inc. and Medtronic. 

References
  1. Kandzari DE. Long-term clinical safety and efficacy: the Orsiro ultrathin bioresorbable polymer sirolimus-eluting stent. Cath Lab Digest. 2019 June; 27(6): 38-39. Available online at https://www.cathlabdigest.com/content/long-term-clinical-safety-and-efficacy-orsiro-ultrathin-bioresorbable-polymer-sirolimus-eluting-stent. Accessed April 14, 2020.
  2. Kandzari DE, Koolen JJ, Doros G, et al. Ultrathin bioresorbable polymer sirolimus-eluting stents versus thin durable polymer everolimus-eluting stents for coronary revascularization: three-year outcomes from the randomized BIOFLOW V trial. J Am Coll Cardiol Intv. 2020 Feb 23. Epublished doi:10.1016/j.jcin.2020.02.019.
  3. Mattke S, Hanson M, Bentele M, Kandzari DE. Cost and mortality implications of lower event rates after implantation of an ultrathin strut coronary stent compared with a thin strut stent over four years. Cardiovasc Revasc Med. 2019 Dec 18. pii: S1553-8389(19)30816-4. doi: 10.1016/j.carrev.2019.12.018.